Kidney disease is ranked fourth among the major diseases in the United States afflicting over 20 million Americans. More than 90,000 patients die each year because of kidney diseases. In recent years the number of chronic kidney failure patients has increased about 11 percent annually. About 80,000 Americans on dialysis die of various complications each year and more than 27,000 are on waiting lists for kidney transplants each year with only about 11,000 of these patients receiving transplants. Further, nearly 350,000 Americans suffer from end stage renal disease (ESRD), which is the final stage in chronic renal failure.
In normal, healthy humans, metabolic waste nitrogen is primarily excreted via the kidneys as urea, uric acid creatinine, etc. in the urine. However, in individuals with kidney disease, as well as a number of other diseases such as inborn errors in urea cycle enzyme deficit, waste nitrogen accumulates in the body thereby manifesting toxic symptoms. Hyperammonium can lead to mental retardation and, in severe cases, coma.
Uremic toxins accumulate during development of renal failure. Uremic toxins are generated from a number of sources including diet, chemotherapy, diabetes and metabolic disorders. Any number of low-carbohydrate and high-protein diets is being touted today as the answer for weight problems and obesity. More and more people are cutting carbohydrates from their diets and eating more meat, fish, poultry and dairy products to reduce body fat. However, too much protein can lead to kidney problems and urinary tract problems, affecting a person's ability to stay properly hydrated during times of increased activity which also increases the risk of heat stress. Additionally, high-protein diets actually accelerate calcium loss form bones and increase the risk of osteoporosis, leading to an increase in stress fractures, ankle fractures and vertebral fractures. High protein diets also lead to the condition called ketosis, or the accumulation of ketone bodies.
Currently hemo- or peritoneal-dialysis and renal transplant are the only treatment modalities. However, the economic costs of these treatment modalities are extremely high. For example, in 1996 in the United States alone, the annual cast of ESRD treatment was over 14 billion dollars. In developing and underdeveloped countries with low health care budgets, ESRD patients are deprived access to such treatments due to their high costs. Accordingly, there is a need for alternative modalities of treatment for uremia.
A number of treatment attempts have been based on the use of the bowel as a substitute for kidney function. During a normal digestive process the gastrointestinal tract delivers nutrients and water to the bloodstream and eliminates some waste products and undigested materials through the bowel. The intestinal wall regulates absorption of nutrients, electrolytes, water and certain digestive aiding substances such as bile acids. The intestinal wall also acts as a semi-permeable membrane allowing small molecules to pass from the intestinal tract into the bloodstream and preventing larger molecules from entering the circulation.
Nitrogenous wastes such as urea, uric acid, creatinine and uric acid, along with several other small and medium molecular weight compounds, flow into the small intestine and equilibrate across the small intestine epithelium. Studies of intestinal dialysis have shown a daily flow of 71 grams of urea, 2.9 grams of creatinine, 2.5 grams of uric acid and 2.0 grams of phosphate into the intestinal fluid (Sparks (1975) Kidney Int. Suppl. (Suppl 3) 7:373-376). Accordingly, various invasive and noninvasive attempts including external gut fistula, intestinal dialysis, induced diarrhea, and administration of oral sorbents and/or encapsulated urease enzyme have been made to extract uremic waste from the gastrointestinal tract (Twiss and Kolff (1951) JAMA 146:1019-1022; Clark, et al. (1962) Trans. Am. Soc. Artif. Intrn. Organs 8:246-251; Pateras, et al. (1965) Trans. Am. Soc. Artif. Intrn. Organs 11:292-295; Shimizu, et al. (1955) Chemical Abstracts 103:129004; Kjellstrand, et al. (1981) Trans. Am. Soc. Artif. Intern. Organs 27:24-29; Kolff (1976) Kidney Int. 10:S211-S214).
In addition, genetically engineered E. herbicola cells have been encapsulated and demonstrated to convert ammonia into usable amino acids for the cells before being eliminated via the bowel. Microencapsulated genetically engineered E. coli DH5 cells have also been shown to be effective in removal of urea and ammonia in an in vitro system and in a uremic rat animal model (Prakash and Chang (1955) Biotechnology and Bioengineering 46:621-26; Prakash and Chang (1996) Nature Med. 2:883-887). However, administration of genetically engineered bacteria poses regulatory and safety concerns and raises ethical issues which may lead to noncompliance by patients.
The human gastrointestinal tract harbors a complex microbial ecosystem containing a large number and variety of bacteria. The resident bacterial population in the human gastrointestinal tract has a major impact on gastrointestinal function and thereby on human health and well-being. Among these, some bacteria are opportunistic and considered to be detrimental and cause adverse conditions such as diarrhea, infections, gastroenteritis and endotoxaemia, while some bacteria species are considered as “probiotic”, in that they perform beneficial functions for the human organism (Holzapfel, et al. (1998) Int. J. Food Microbiol. 41(2): 85-101).
Among the probiotic bacteria, Bifidobacteria species are the most prominent. Bifidobacteria species, when in live and viable form, stimulate the immune system and exert a competitive exclusion of pathogenic and putrefactive bacteria, reduce the amounts of ammonia and cholesterol in the blood, and promote absorption of minerals. In addition, Bifidobacteria have been suggested to exert a preventive action against colon cancer, by reducing the activity of some enzymes that convert procarcinogen substances into carcinogen substances (von Wright, et al. (1999) Eur. J. Gastroenterol. Hepatol. 11(11):1195-1198).
The lactic bacteria include Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum and Streptococcus faecium. Streptococcus thermophilus are also considered probiotic. These bacteria produce antagonist effects against pathogenic microorganisms, stimulate the immune system, improve lactose digestion, perform a lypolytic activity making fats more digestible, reduce plasmatic values of cholesterol, protect the intestinal mucosa ensuring an even assimilation of the nutritive substances, produce polysaccharides that are active on some tumors, and reduce viability of some enzyme-producing microorganisms catalysing conversion of procarcinogen substances into carcinogenic substances.
It is believed that the probiotic bacteria exert their effects in a synergistic manner to curtail and retard the growth of pathogenic/detrimental bacteria of the gut (Marteau, et al. (2001) Am. J. Clin. Nutr. 73(2 Suppl):430S-436S; Cummings, et al. (2001) Am. J. Clin. Nutr. 73(2 Suppl):415S-420S).
The intestinal bacteria flora can be reduced become unbalanced or be eliminated in patients undergoing antibiotic treatment and other therapies, and in individuals suffering from inflammatory intestinal diseases, kidney disease and liver disease. In addition, it has been shown that during normal aging the Bifidobacteria population is reduced while the concentration of pathogenic and putrefactive bacteria concamitantly increases (Orrhage, et al. (2000) Drugs Exp. Clin. Res. 26(3):95-111).
It is also known that beneficial effects of microbes such as the Bifidobacterium species are in part due to their ability to ferment nondigestible sugars, known as prebiotics, present in the colon. A prebiotic is a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or the activity of one or a limited number of bacteria in the colon. Prebiotics are typically thought of as carbohydrates of relatively short chain length. Prebiotics are like other carbohydrates that reach the cecum, such as nonstarch polysaccharides, sugar alcohols, and resistant starch, in being substrates for fermentation. They are, however, distinctive in their selective effect on the microflora and are effective only when they reach the cecum (Bezkorovainy (2001) Am. J. Clin. Nutr. 73(2 Suppl):399S-405S).
U.S. Pat. No. 5,733,568 teaches the use of microencapsulated Lactobacillus bacteria for treatment of antibiotic associated or other acute and chronic diarrhea as well as for skin and vaginal yeast infections. The microencapsulation is said to prevent inactivation of the bacillus and to deliver it to the intestine as well as to avoid lactose intolerance seen in said diarrheas.
U.S. Pat. No. 5,032,399 teaches the use of species of Lactobacillus acidophilus to adhere to intestinal mucosa and thereby reduce gastrointestinal side effects of antibiotic therapy that reduces beneficial bacteria population.
U.S. Pat. No. 5,145,697 discloses powdered yogurt formulations containing S. thermophilus. Similarly, U.S. Pat. No. 4,427,701 teaches a frozen yogurt product containing S. thermophilus. However, these references do not teach any special features of the S. thermophilus strain employed.
U.S. Pat. No. 5,531,988 teaches, in addition to beneficial bacteria, use of immunoglobulin in the composition as a dietary supplement.
U.S. Pat. No. 5,840,318 also teaches a beneficial bacterial composition that can modulate the immune system of animals.
U.S. Pat. No. 6,080,401 teaches that the speed of treatment using herbal medicines can be improved by combining the herbal medicine with probiotic microorganisms. However, this reference does not teach any special features of the probiotics employed.
Use of probiotics such as Lactobacillus acidophilus has been suggested to curtail the bacterial overgrowth and the accumulation of uremic toxins and carcinogenic compounds. Unabsorbable carbohydrate in the diet of uremic patients has also been shown to increase fecal nitrogen. Use of lactulose and dietary fiber has also been shown to reduce plasma urea 11 to 27% and increase fecal nitrogen excretion to 39 to 62% (Wrong (1997) Nature Medicine 2-3).